JP5580598B2 - γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法 - Google Patents

γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法 Download PDF

Info

Publication number: JP5580598B2
Authority: JP; Japan
Prior art keywords: epha7; secretase; cleavage; candidate compound; compound
Prior art date: 2007-11-15
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Fee Related

Application number

JP2009541201A

Other languages

English (en)

Japanese (ja)

Other versions

JPWO2009064006A1 (ja

Inventor

英二井上

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Eisai R&D Management Co Ltd

Original Assignee

Eisai R&D Management Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2007-11-15

Filing date

2008-11-17

Publication date

2014-08-27

2008-11-17 Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd

2011-03-31 Publication of JPWO2009064006A1 publication Critical patent/JPWO2009064006A1/ja

2014-08-27 Application granted granted Critical

2014-08-27 Publication of JP5580598B2 publication Critical patent/JP5580598B2/ja

Status Expired - Fee Related legal-status Critical Current

2028-11-17 Anticipated expiration legal-status Critical

Links

102100021606 Ephrin type-A receptor 7 Human genes 0.000 title claims description 274
102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 title claims description 178
108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 title claims description 178
238000000034 method Methods 0.000 title claims description 90
238000012216 screening Methods 0.000 title claims description 24
239000000758 substrate Substances 0.000 title claims description 22
108010055153 EphA7 Receptor Proteins 0.000 title claims 25
150000001875 compounds Chemical class 0.000 claims description 120
238000003776 cleavage reaction Methods 0.000 claims description 110
230000007017 scission Effects 0.000 claims description 108
108090000765 processed proteins & peptides Proteins 0.000 claims description 70
102000004196 processed proteins & peptides Human genes 0.000 claims description 62
229920001184 polypeptide Polymers 0.000 claims description 57
230000000694 effects Effects 0.000 claims description 50
238000012545 processing Methods 0.000 claims description 39
239000012634 fragment Substances 0.000 claims description 32
239000000203 mixture Substances 0.000 claims description 29
238000006731 degradation reaction Methods 0.000 claims description 17
230000015556 catabolic process Effects 0.000 claims description 16
239000003112 inhibitor Substances 0.000 claims description 8
238000003556 assay Methods 0.000 claims description 5
230000002829 reductive effect Effects 0.000 claims description 3
238000007689 inspection Methods 0.000 claims 1
101000898708 Homo sapiens Ephrin type-A receptor 7 Proteins 0.000 description 254
210000004027 cell Anatomy 0.000 description 77
239000000047 product Substances 0.000 description 43
DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 42
101710137189 Amyloid-beta A4 protein Proteins 0.000 description 41
101710151993 Amyloid-beta precursor protein Proteins 0.000 description 41
102100022704 Amyloid-beta precursor protein Human genes 0.000 description 40
108010070047 Notch Receptors Proteins 0.000 description 32
102000005650 Notch Receptors Human genes 0.000 description 32
208000024827 Alzheimer disease Diseases 0.000 description 28
102000040430 polynucleotide Human genes 0.000 description 28
108091033319 polynucleotide Proteins 0.000 description 28
239000002157 polynucleotide Substances 0.000 description 28
108090000623 proteins and genes Proteins 0.000 description 26
-1 inorganic acid salt Chemical class 0.000 description 20
208000024891 symptom Diseases 0.000 description 19
241001465754 Metazoa Species 0.000 description 18
235000001014 amino acid Nutrition 0.000 description 16
229940024606 amino acid Drugs 0.000 description 16
150000001413 amino acids Chemical class 0.000 description 14
HVLSXIKZNLPZJJ-TXZCQADKSA-N HA peptide Chemical group C([C@@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HVLSXIKZNLPZJJ-TXZCQADKSA-N 0.000 description 13
239000003540 gamma secretase inhibitor Substances 0.000 description 13
JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
238000011282 treatment Methods 0.000 description 12
229940125373 Gamma-Secretase Inhibitor Drugs 0.000 description 11
DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 11
201000010099 disease Diseases 0.000 description 11
150000003839 salts Chemical class 0.000 description 11
241000124008 Mammalia Species 0.000 description 10
125000003275 alpha amino acid group Chemical group 0.000 description 10
210000004556 brain Anatomy 0.000 description 10
239000013604 expression vector Substances 0.000 description 10
239000002585 base Substances 0.000 description 9
238000004519 manufacturing process Methods 0.000 description 9
230000001575 pathological effect Effects 0.000 description 9
238000000746 purification Methods 0.000 description 9
241000699666 Mus <mouse, genus> Species 0.000 description 8
125000000539 amino acid group Chemical group 0.000 description 8
210000000170 cell membrane Anatomy 0.000 description 8
210000002569 neuron Anatomy 0.000 description 8
238000002360 preparation method Methods 0.000 description 8
235000018102 proteins Nutrition 0.000 description 8
102000004169 proteins and genes Human genes 0.000 description 8
238000001890 transfection Methods 0.000 description 8
108020004414 DNA Proteins 0.000 description 7
210000004900 c-terminal fragment Anatomy 0.000 description 7
210000004899 c-terminal region Anatomy 0.000 description 7
239000003814 drug Substances 0.000 description 7
238000009396 hybridization Methods 0.000 description 7
239000012528 membrane Substances 0.000 description 7
102000013455 Amyloid beta-Peptides Human genes 0.000 description 6
108010090849 Amyloid beta-Peptides Proteins 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
108091028043 Nucleic acid sequence Proteins 0.000 description 6
239000013592 cell lysate Substances 0.000 description 6
238000006243 chemical reaction Methods 0.000 description 6
230000006870 function Effects 0.000 description 6
238000001727 in vivo Methods 0.000 description 6
239000000843 powder Substances 0.000 description 6
239000000523 sample Substances 0.000 description 6
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
235000014113 dietary fatty acids Nutrition 0.000 description 5
238000011156 evaluation Methods 0.000 description 5
239000000194 fatty acid Substances 0.000 description 5
229930195729 fatty acid Natural products 0.000 description 5
230000003834 intracellular effect Effects 0.000 description 5
239000008194 pharmaceutical composition Substances 0.000 description 5
239000003826 tablet Substances 0.000 description 5
238000012360 testing method Methods 0.000 description 5
206010012289 Dementia Diseases 0.000 description 4
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
101000579647 Penaeus vannamei Penaeidin-2a Proteins 0.000 description 4
229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
150000001298 alcohols Chemical class 0.000 description 4
108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 4
101150089041 aph-1 gene Proteins 0.000 description 4
210000004671 cell-free system Anatomy 0.000 description 4
239000003086 colorant Substances 0.000 description 4
238000012258 culturing Methods 0.000 description 4
230000014509 gene expression Effects 0.000 description 4
239000008187 granular material Substances 0.000 description 4
HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 4
210000004408 hybridoma Anatomy 0.000 description 4
239000000463 material Substances 0.000 description 4
102000046701 nicastrin Human genes 0.000 description 4
108700022821 nicastrin Proteins 0.000 description 4
239000002904 solvent Substances 0.000 description 4
239000000126 substance Substances 0.000 description 4
210000000225 synapse Anatomy 0.000 description 4
229940124597 therapeutic agent Drugs 0.000 description 4
239000004474 valine Substances 0.000 description 4
238000001262 western blot Methods 0.000 description 4
206010003445 Ascites Diseases 0.000 description 3
108010031111 EBV-encoded nuclear antigen 1 Proteins 0.000 description 3
241000196324 Embryophyta Species 0.000 description 3
102000004190 Enzymes Human genes 0.000 description 3
108090000790 Enzymes Proteins 0.000 description 3
241000283073 Equus caballus Species 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
101710154606 Hemagglutinin Proteins 0.000 description 3
208000026139 Memory disease Diseases 0.000 description 3
101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
102100022033 Presenilin-1 Human genes 0.000 description 3
102000015499 Presenilins Human genes 0.000 description 3
108010050254 Presenilins Proteins 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
101710176177 Protein A56 Proteins 0.000 description 3
101100065498 Rattus norvegicus Epha7 gene Proteins 0.000 description 3
239000012190 activator Substances 0.000 description 3
239000000427 antigen Substances 0.000 description 3
108091007433 antigens Proteins 0.000 description 3
102000036639 antigens Human genes 0.000 description 3
238000002869 basic local alignment search tool Methods 0.000 description 3
239000011230 binding agent Substances 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
239000000872 buffer Substances 0.000 description 3
230000008859 change Effects 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
239000002299 complementary DNA Substances 0.000 description 3
238000007796 conventional method Methods 0.000 description 3
239000012228 culture supernatant Substances 0.000 description 3
230000007423 decrease Effects 0.000 description 3
239000007884 disintegrant Substances 0.000 description 3
239000002552 dosage form Substances 0.000 description 3
230000002255 enzymatic effect Effects 0.000 description 3
238000002474 experimental method Methods 0.000 description 3
239000000796 flavoring agent Substances 0.000 description 3
235000013355 food flavoring agent Nutrition 0.000 description 3
230000004927 fusion Effects 0.000 description 3
235000011187 glycerol Nutrition 0.000 description 3
239000000185 hemagglutinin Substances 0.000 description 3
238000000338 in vitro Methods 0.000 description 3
238000012423 maintenance Methods 0.000 description 3
244000005700 microbiome Species 0.000 description 3
239000002773 nucleotide Substances 0.000 description 3
125000003729 nucleotide group Chemical group 0.000 description 3
239000003921 oil Substances 0.000 description 3
235000019198 oils Nutrition 0.000 description 3
230000036961 partial effect Effects 0.000 description 3
239000000546 pharmaceutical excipient Substances 0.000 description 3
239000013612 plasmid Substances 0.000 description 3
229920001223 polyethylene glycol Polymers 0.000 description 3
239000000243 solution Substances 0.000 description 3
238000006467 substitution reaction Methods 0.000 description 3
239000004094 surface-active agent Substances 0.000 description 3
YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 2
208000037259 Amyloid Plaque Diseases 0.000 description 2
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
241000282472 Canis lupus familiaris Species 0.000 description 2
FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
DWJXYEABWRJFSP-XOBRGWDASA-N DAPT Chemical compound N([C@@H](C)C(=O)N[C@H](C(=O)OC(C)(C)C)C=1C=CC=CC=1)C(=O)CC1=CC(F)=CC(F)=C1 DWJXYEABWRJFSP-XOBRGWDASA-N 0.000 description 2
239000006144 Dulbecco’s modiﬁed Eagle's medium Substances 0.000 description 2
241000588724 Escherichia coli Species 0.000 description 2
108010010803 Gelatin Proteins 0.000 description 2
102000005720 Glutathione transferase Human genes 0.000 description 2
108010070675 Glutathione transferase Proteins 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
101000617536 Homo sapiens Presenilin-1 Proteins 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
235000006679 Mentha X verticillata Nutrition 0.000 description 2
235000002899 Mentha suaveolens Nutrition 0.000 description 2
235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
241000699670 Mus sp. Species 0.000 description 2
108700037638 Neurogenic locus notch homolog protein 1 Proteins 0.000 description 2
102100023181 Neurogenic locus notch homolog protein 1 Human genes 0.000 description 2
241000289371 Ornithorhynchus anatinus Species 0.000 description 2
206010035226 Plasma cell myeloma Diseases 0.000 description 2
239000002202 Polyethylene glycol Substances 0.000 description 2
108010036933 Presenilin-1 Proteins 0.000 description 2
108010036908 Presenilin-2 Proteins 0.000 description 2
102000012419 Presenilin-2 Human genes 0.000 description 2
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 2
108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 2
240000004808 Saccharomyces cerevisiae Species 0.000 description 2
229920002125 Sokalan® Polymers 0.000 description 2
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
238000001042 affinity chromatography Methods 0.000 description 2
BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 2
210000004102 animal cell Anatomy 0.000 description 2
239000010775 animal oil Substances 0.000 description 2
239000003963 antioxidant agent Substances 0.000 description 2
238000003149 assay kit Methods 0.000 description 2
230000037396 body weight Effects 0.000 description 2
239000002775 capsule Substances 0.000 description 2
235000010980 cellulose Nutrition 0.000 description 2
239000001913 cellulose Substances 0.000 description 2
229920002678 cellulose Polymers 0.000 description 2
238000005119 centrifugation Methods 0.000 description 2
210000003710 cerebral cortex Anatomy 0.000 description 2
238000007385 chemical modification Methods 0.000 description 2
210000000349 chromosome Anatomy 0.000 description 2
238000010367 cloning Methods 0.000 description 2
239000000470 constituent Substances 0.000 description 2
210000004748 cultured cell Anatomy 0.000 description 2
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
235000018417 cysteine Nutrition 0.000 description 2
238000001514 detection method Methods 0.000 description 2
239000003599 detergent Substances 0.000 description 2
NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
239000003937 drug carrier Substances 0.000 description 2
238000011977 dual antiplatelet therapy Methods 0.000 description 2
239000003889 eye drop Substances 0.000 description 2
229940012356 eye drops Drugs 0.000 description 2
208000015756 familial Alzheimer disease Diseases 0.000 description 2
238000005194 fractionation Methods 0.000 description 2
239000008273 gelatin Substances 0.000 description 2
229920000159 gelatin Polymers 0.000 description 2
229940014259 gelatin Drugs 0.000 description 2
235000019322 gelatine Nutrition 0.000 description 2
235000011852 gelatine desserts Nutrition 0.000 description 2
FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
238000013537 high throughput screening Methods 0.000 description 2
230000000971 hippocampal effect Effects 0.000 description 2
125000001165 hydrophobic group Chemical group 0.000 description 2
239000000815 hypotonic solution Substances 0.000 description 2
238000001597 immobilized metal affinity chromatography Methods 0.000 description 2
230000002163 immunogen Effects 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
238000010253 intravenous injection Methods 0.000 description 2
238000004255 ion exchange chromatography Methods 0.000 description 2
238000002955 isolation Methods 0.000 description 2
229960000310 isoleucine Drugs 0.000 description 2
AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
239000000314 lubricant Substances 0.000 description 2
230000002934 lysing effect Effects 0.000 description 2
210000004962 mammalian cell Anatomy 0.000 description 2
239000002609 medium Substances 0.000 description 2
229920000609 methyl cellulose Polymers 0.000 description 2
235000010981 methylcellulose Nutrition 0.000 description 2
239000001923 methylcellulose Substances 0.000 description 2
230000004048 modification Effects 0.000 description 2
238000012986 modification Methods 0.000 description 2
230000035772 mutation Effects 0.000 description 2
201000000050 myeloid neoplasm Diseases 0.000 description 2
210000002682 neurofibrillary tangle Anatomy 0.000 description 2
WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
229920001451 polypropylene glycol Polymers 0.000 description 2
229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
239000001267 polyvinylpyrrolidone Substances 0.000 description 2
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
230000001242 postsynaptic effect Effects 0.000 description 2
238000001556 precipitation Methods 0.000 description 2
239000003755 preservative agent Substances 0.000 description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
230000017854 proteolysis Effects 0.000 description 2
239000008213 purified water Substances 0.000 description 2
239000002994 raw material Substances 0.000 description 2
210000002966 serum Anatomy 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
239000012453 solvate Substances 0.000 description 2
239000000600 sorbitol Substances 0.000 description 2
PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
239000003381 stabilizer Substances 0.000 description 2
235000000346 sugar Nutrition 0.000 description 2
150000005846 sugar alcohols Polymers 0.000 description 2
239000006188 syrup Substances 0.000 description 2
235000020357 syrup Nutrition 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
230000009466 transformation Effects 0.000 description 2
230000009261 transgenic effect Effects 0.000 description 2
235000015112 vegetable and seed oil Nutrition 0.000 description 2
239000008158 vegetable oil Substances 0.000 description 2
238000005406 washing Methods 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
229920003169 water-soluble polymer Polymers 0.000 description 2
MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
BWUCMIRXOBWHQZ-GJBWKJBBSA-N 2-aminoacetic acid (2S)-2-amino-3-phenylpropanoic acid (2S)-2,6-diaminohexanoic acid (2S)-pyrrolidine-2-carboxylic acid Chemical compound NCC(O)=O.OC(=O)[C@@H]1CCCN1.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](N)CC1=CC=CC=C1 BWUCMIRXOBWHQZ-GJBWKJBBSA-N 0.000 description 1
BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
BGRXBNZMPMGLQI-UHFFFAOYSA-N 2-octyldodecyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(CCCCCCCC)CCCCCCCCCC BGRXBNZMPMGLQI-UHFFFAOYSA-N 0.000 description 1
FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
244000215068 Acacia senegal Species 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
208000000044 Amnesia Diseases 0.000 description 1
206010059245 Angiopathy Diseases 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
102000035101 Aspartic proteases Human genes 0.000 description 1
108091005502 Aspartic proteases Proteins 0.000 description 1
241000416162 Astragalus gummifer Species 0.000 description 1
206010003591 Ataxia Diseases 0.000 description 1
206010003694 Atrophy Diseases 0.000 description 1
241000713842 Avian sarcoma virus Species 0.000 description 1
239000012583 B-27 Supplement Substances 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
241000255789 Bombyx mori Species 0.000 description 1
241000409811 Bombyx mori nucleopolyhedrovirus Species 0.000 description 1
241000283690 Bos taurus Species 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
241000824799 Canis lupus dingo Species 0.000 description 1
239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
241000701489 Cauliflower mosaic virus Species 0.000 description 1
241000700199 Cavia porcellus Species 0.000 description 1
102000000844 Cell Surface Receptors Human genes 0.000 description 1
108010001857 Cell Surface Receptors Proteins 0.000 description 1
241000282693 Cercopithecidae Species 0.000 description 1
244000223760 Cinnamomum zeylanicum Species 0.000 description 1
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
241000699800 Cricetinae Species 0.000 description 1
241000699802 Cricetulus griseus Species 0.000 description 1
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
230000004544 DNA amplification Effects 0.000 description 1
229920002307 Dextran Polymers 0.000 description 1
229920001353 Dextrin Polymers 0.000 description 1
239000004375 Dextrin Substances 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
239000001856 Ethyl cellulose Substances 0.000 description 1
ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
229930091371 Fructose Natural products 0.000 description 1
RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
239000005715 Fructose Substances 0.000 description 1
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
208000032612 Glial tumor Diseases 0.000 description 1
206010018338 Glioma Diseases 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
229920000084 Gum arabic Polymers 0.000 description 1
239000007995 HEPES buffer Substances 0.000 description 1
208000031886 HIV Infections Diseases 0.000 description 1
229920000209 Hexadimethrine bromide Polymers 0.000 description 1
241000238631 Hexapoda Species 0.000 description 1
241000282412 Homo Species 0.000 description 1
101000978766 Homo sapiens Neurogenic locus notch homolog protein 1 Proteins 0.000 description 1
101000617546 Homo sapiens Presenilin-2 Proteins 0.000 description 1
241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
206010061598 Immunodeficiency Diseases 0.000 description 1
208000029462 Immunodeficiency disease Diseases 0.000 description 1
102000004877 Insulin Human genes 0.000 description 1
108090001061 Insulin Proteins 0.000 description 1
XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
229930182816 L-glutamine Natural products 0.000 description 1
ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
239000012097 Lipofectamine 2000 Substances 0.000 description 1
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
239000004472 Lysine Substances 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 1
229930195725 Mannitol Natural products 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
241000713333 Mouse mammary tumor virus Species 0.000 description 1
101000978776 Mus musculus Neurogenic locus notch homolog protein 1 Proteins 0.000 description 1
101000617548 Mus musculus Presenilin-2 Proteins 0.000 description 1
MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
229910002651 NO3 Inorganic materials 0.000 description 1
206010029350 Neurotoxicity Diseases 0.000 description 1
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
241000283973 Oryctolagus cuniculus Species 0.000 description 1
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
238000009004 PCR Kit Methods 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
102000035195 Peptidases Human genes 0.000 description 1
108091005804 Peptidases Proteins 0.000 description 1
108010067902 Peptide Library Proteins 0.000 description 1
ZPHBZEQOLSRPAK-UHFFFAOYSA-N Phosphoramidon Natural products C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O ZPHBZEQOLSRPAK-UHFFFAOYSA-N 0.000 description 1
108091000080 Phosphotransferase Proteins 0.000 description 1
101710182846 Polyhedrin Proteins 0.000 description 1
229920001214 Polysorbate 60 Polymers 0.000 description 1
239000004372 Polyvinyl alcohol Substances 0.000 description 1
239000004365 Protease Substances 0.000 description 1
229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
102000001708 Protein Isoforms Human genes 0.000 description 1
108010029485 Protein Isoforms Proteins 0.000 description 1
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
241000700159 Rattus Species 0.000 description 1
101000577196 Rattus norvegicus Neurogenic locus notch homolog protein 1 Proteins 0.000 description 1
101000617533 Rattus norvegicus Presenilin-1 Proteins 0.000 description 1
101000617543 Rattus norvegicus Presenilin-2 Proteins 0.000 description 1
MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
102000005686 Serum Globulins Human genes 0.000 description 1
108010045362 Serum Globulins Proteins 0.000 description 1
229920001800 Shellac Polymers 0.000 description 1
XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
229930006000 Sucrose Natural products 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
241000282898 Sus scrofa Species 0.000 description 1
235000009470 Theobroma cacao Nutrition 0.000 description 1
244000299461 Theobroma cacao Species 0.000 description 1
AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
239000004473 Threonine Substances 0.000 description 1
206010044221 Toxic encephalopathy Diseases 0.000 description 1
229920001615 Tragacanth Polymers 0.000 description 1
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
230000002159 abnormal effect Effects 0.000 description 1
229940124532 absorption promoter Drugs 0.000 description 1
235000010489 acacia gum Nutrition 0.000 description 1
239000000205 acacia gum Substances 0.000 description 1
238000009825 accumulation Methods 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
230000009471 action Effects 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000010933 acylation Effects 0.000 description 1
238000005917 acylation reaction Methods 0.000 description 1
239000002671 adjuvant Substances 0.000 description 1
230000002411 adverse Effects 0.000 description 1
239000008272 agar Substances 0.000 description 1
235000010419 agar Nutrition 0.000 description 1
239000000556 agonist Substances 0.000 description 1
235000004279 alanine Nutrition 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
230000009435 amidation Effects 0.000 description 1
238000007112 amidation reaction Methods 0.000 description 1
229910052921 ammonium sulfate Inorganic materials 0.000 description 1
235000011130 ammonium sulphate Nutrition 0.000 description 1
230000003321 amplification Effects 0.000 description 1
208000007502 anemia Diseases 0.000 description 1
238000010171 animal model Methods 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
230000000844 anti-bacterial effect Effects 0.000 description 1
229940121363 anti-inflammatory agent Drugs 0.000 description 1
239000002260 anti-inflammatory agent Substances 0.000 description 1
230000002421 anti-septic effect Effects 0.000 description 1
210000000628 antibody-producing cell Anatomy 0.000 description 1
239000003429 antifungal agent Substances 0.000 description 1
229940121375 antifungal agent Drugs 0.000 description 1
239000004599 antimicrobial Substances 0.000 description 1
201000007201 aphasia Diseases 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
235000009582 asparagine Nutrition 0.000 description 1
229960001230 asparagine Drugs 0.000 description 1
229940009098 aspartate Drugs 0.000 description 1
235000003704 aspartic acid Nutrition 0.000 description 1
230000037444 atrophy Effects 0.000 description 1
230000001580 bacterial effect Effects 0.000 description 1
230000037358 bacterial metabolism Effects 0.000 description 1
239000003899 bactericide agent Substances 0.000 description 1
235000015278 beef Nutrition 0.000 description 1
229940077388 benzenesulfonate Drugs 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
229960002685 biotin Drugs 0.000 description 1
235000020958 biotin Nutrition 0.000 description 1
239000011616 biotin Substances 0.000 description 1
229920001400 block copolymer Polymers 0.000 description 1
230000017531 blood circulation Effects 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
239000004067 bulking agent Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000011575 calcium Substances 0.000 description 1
235000001465 calcium Nutrition 0.000 description 1
229910000019 calcium carbonate Inorganic materials 0.000 description 1
FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
239000001354 calcium citrate Substances 0.000 description 1
239000001506 calcium phosphate Substances 0.000 description 1
229910000389 calcium phosphate Inorganic materials 0.000 description 1
235000011010 calcium phosphates Nutrition 0.000 description 1
159000000007 calcium salts Chemical class 0.000 description 1
MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
239000001768 carboxy methyl cellulose Substances 0.000 description 1
150000007942 carboxylates Chemical class 0.000 description 1
239000008112 carboxymethyl-cellulose Substances 0.000 description 1
239000000969 carrier Substances 0.000 description 1
239000004359 castor oil Substances 0.000 description 1
235000019438 castor oil Nutrition 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
210000003169 central nervous system Anatomy 0.000 description 1
210000001175 cerebrospinal fluid Anatomy 0.000 description 1
229940082500 cetostearyl alcohol Drugs 0.000 description 1
239000002738 chelating agent Substances 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
238000011210 chromatographic step Methods 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
235000017803 cinnamon Nutrition 0.000 description 1
239000002734 clay mineral Substances 0.000 description 1
239000011248 coating agent Substances 0.000 description 1
238000000576 coating method Methods 0.000 description 1
208000030251 communication disease Diseases 0.000 description 1
230000000295 complement effect Effects 0.000 description 1
238000012790 confirmation Methods 0.000 description 1
208000004209 confusion Diseases 0.000 description 1
238000010276 construction Methods 0.000 description 1
239000008120 corn starch Substances 0.000 description 1
239000002537 cosmetic Substances 0.000 description 1
239000007857 degradation product Substances 0.000 description 1
230000000593 degrading effect Effects 0.000 description 1
230000001934 delay Effects 0.000 description 1
210000001787 dendrite Anatomy 0.000 description 1
238000000432 density-gradient centrifugation Methods 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000011161 development Methods 0.000 description 1
230000018109 developmental process Effects 0.000 description 1
235000019425 dextrin Nutrition 0.000 description 1
238000003745 diagnosis Methods 0.000 description 1
SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
208000035475 disorder Diseases 0.000 description 1
206010013395 disorientation Diseases 0.000 description 1
239000002270 dispersing agent Substances 0.000 description 1
229960000735 docosanol Drugs 0.000 description 1
239000006196 drop Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
238000009510 drug design Methods 0.000 description 1
238000007876 drug discovery Methods 0.000 description 1
239000003221 ear drop Substances 0.000 description 1
229940047652 ear drops Drugs 0.000 description 1
208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
238000001962 electrophoresis Methods 0.000 description 1
238000004520 electroporation Methods 0.000 description 1
210000001671 embryonic stem cell Anatomy 0.000 description 1
239000003995 emulsifying agent Substances 0.000 description 1
210000002889 endothelial cell Anatomy 0.000 description 1
239000010696 ester oil Substances 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
235000019325 ethyl cellulose Nutrition 0.000 description 1
229920001249 ethyl cellulose Polymers 0.000 description 1
210000003527 eukaryotic cell Anatomy 0.000 description 1
239000013613 expression plasmid Substances 0.000 description 1
239000003885 eye ointment Substances 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
210000002950 fibroblast Anatomy 0.000 description 1
230000037406 food intake Effects 0.000 description 1
235000012631 food intake Nutrition 0.000 description 1
239000003205 fragrance Substances 0.000 description 1
108020001507 fusion proteins Proteins 0.000 description 1
102000037865 fusion proteins Human genes 0.000 description 1
238000001502 gel electrophoresis Methods 0.000 description 1
238000001641 gel filtration chromatography Methods 0.000 description 1
238000010353 genetic engineering Methods 0.000 description 1
239000008103 glucose Substances 0.000 description 1
229930195712 glutamate Natural products 0.000 description 1
235000013922 glutamic acid Nutrition 0.000 description 1
239000004220 glutamic acid Substances 0.000 description 1
ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
125000005456 glyceride group Chemical group 0.000 description 1
ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
238000003505 heat denaturation Methods 0.000 description 1
230000011132 hemopoiesis Effects 0.000 description 1
UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
238000000265 homogenisation Methods 0.000 description 1
102000045609 human NOTCH1 Human genes 0.000 description 1
102000055060 human PSEN1 Human genes 0.000 description 1
102000055037 human PSEN2 Human genes 0.000 description 1
239000003906 humectant Substances 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
239000008172 hydrogenated vegetable oil Substances 0.000 description 1
230000002209 hydrophobic effect Effects 0.000 description 1
235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
238000012872 hydroxylapatite chromatography Methods 0.000 description 1
235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
239000001863 hydroxypropyl cellulose Substances 0.000 description 1
235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
230000003053 immunization Effects 0.000 description 1
238000003119 immunoblot Methods 0.000 description 1
230000007813 immunodeficiency Effects 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
229940125396 insulin Drugs 0.000 description 1
238000010255 intramuscular injection Methods 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000001155 isoelectric focusing Methods 0.000 description 1
239000007951 isotonicity adjuster Substances 0.000 description 1
239000003410 keratolytic agent Substances 0.000 description 1
238000011813 knockout mouse model Methods 0.000 description 1
239000008101 lactose Substances 0.000 description 1
IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
239000003446 ligand Substances 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
238000001638 lipofection Methods 0.000 description 1
239000002502 liposome Substances 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
229940057995 liquid paraffin Drugs 0.000 description 1
229910003002 lithium salt Inorganic materials 0.000 description 1
159000000002 lithium salts Chemical class 0.000 description 1
230000033001 locomotion Effects 0.000 description 1
239000006210 lotion Substances 0.000 description 1
239000007937 lozenge Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000000594 mannitol Substances 0.000 description 1
235000010355 mannitol Nutrition 0.000 description 1
238000005259 measurement Methods 0.000 description 1
229960003194 meglumine Drugs 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
230000006984 memory degeneration Effects 0.000 description 1
208000023060 memory loss Diseases 0.000 description 1
230000006996 mental state Effects 0.000 description 1
230000002503 metabolic effect Effects 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
229930182817 methionine Natural products 0.000 description 1
238000000520 microinjection Methods 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
238000002156 mixing Methods 0.000 description 1
238000010369 molecular cloning Methods 0.000 description 1
108091007270 mouse presenilin 1 Proteins 0.000 description 1
108010008661 mouse presenilin enhancer 2 Proteins 0.000 description 1
239000003471 mutagenic agent Substances 0.000 description 1
231100000707 mutagenic chemical Toxicity 0.000 description 1
230000003505 mutagenic effect Effects 0.000 description 1
JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
210000004898 n-terminal fragment Anatomy 0.000 description 1
239000007923 nasal drop Substances 0.000 description 1
229940100662 nasal drops Drugs 0.000 description 1
230000004770 neurodegeneration Effects 0.000 description 1
210000004498 neuroglial cell Anatomy 0.000 description 1
230000016273 neuron death Effects 0.000 description 1
230000007135 neurotoxicity Effects 0.000 description 1
231100000228 neurotoxicity Toxicity 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
238000003199 nucleic acid amplification method Methods 0.000 description 1
102000039446 nucleic acids Human genes 0.000 description 1
108020004707 nucleic acids Proteins 0.000 description 1
150000007523 nucleic acids Chemical class 0.000 description 1
229960002446 octanoic acid Drugs 0.000 description 1
229940073665 octyldodecyl myristate Drugs 0.000 description 1
239000002674 ointment Substances 0.000 description 1
210000000287 oocyte Anatomy 0.000 description 1
238000005457 optimization Methods 0.000 description 1
210000001672 ovary Anatomy 0.000 description 1
239000003002 pH adjusting agent Substances 0.000 description 1
239000012188 paraffin wax Substances 0.000 description 1
235000010987 pectin Nutrition 0.000 description 1
239000001814 pectin Substances 0.000 description 1
229920001277 pectin Polymers 0.000 description 1
239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
238000010647 peptide synthesis reaction Methods 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
150000003904 phospholipids Chemical class 0.000 description 1
BWSDNRQVTFZQQD-AYVHNPTNSA-N phosphoramidon Chemical compound O([P@@](O)(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC=1[C]2C=CC=CC2=NC=1)C(O)=O)[C@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@@H]1O BWSDNRQVTFZQQD-AYVHNPTNSA-N 0.000 description 1
108010072906 phosphoramidon Proteins 0.000 description 1
102000020233 phosphotransferase Human genes 0.000 description 1
230000001766 physiological effect Effects 0.000 description 1
238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
239000004584 polyacrylic acid Substances 0.000 description 1
229920000728 polyester Polymers 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
229920005862 polyol Polymers 0.000 description 1
150000003077 polyols Chemical class 0.000 description 1
229920002451 polyvinyl alcohol Polymers 0.000 description 1
229920001289 polyvinyl ether Polymers 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000003825 pressing Methods 0.000 description 1
230000008569 process Effects 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000002731 protein assay Methods 0.000 description 1
238000001742 protein purification Methods 0.000 description 1
210000001938 protoplast Anatomy 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
108700010085 rat Aph-1 Proteins 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
230000006798 recombination Effects 0.000 description 1
238000005215 recombination Methods 0.000 description 1
230000009467 reduction Effects 0.000 description 1
230000001177 retroviral effect Effects 0.000 description 1
238000004366 reverse phase liquid chromatography Methods 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
239000004208 shellac Substances 0.000 description 1
229940113147 shellac Drugs 0.000 description 1
ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
235000013874 shellac Nutrition 0.000 description 1
239000010703 silicon Substances 0.000 description 1
229910052710 silicon Inorganic materials 0.000 description 1
235000012239 silicon dioxide Nutrition 0.000 description 1
229920002545 silicone oil Polymers 0.000 description 1
229920002050 silicone resin Polymers 0.000 description 1
238000002741 site-directed mutagenesis Methods 0.000 description 1
150000003384 small molecules Chemical class 0.000 description 1
239000001488 sodium phosphate Substances 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000002689 soil Substances 0.000 description 1
239000007787 solid Substances 0.000 description 1
235000012424 soybean oil Nutrition 0.000 description 1
239000003549 soybean oil Substances 0.000 description 1
241000894007 species Species 0.000 description 1
229940032094 squalane Drugs 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000005720 sucrose Substances 0.000 description 1
238000009495 sugar coating Methods 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
239000000829 suppository Substances 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
210000002182 synaptic membrane Anatomy 0.000 description 1
230000005062 synaptic transmission Effects 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
239000003760 tallow Substances 0.000 description 1
229940095064 tartrate Drugs 0.000 description 1
OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
235000010487 tragacanth Nutrition 0.000 description 1
239000000196 tragacanth Substances 0.000 description 1
229940116362 tragacanth Drugs 0.000 description 1
230000002103 transcriptional effect Effects 0.000 description 1
230000001131 transforming effect Effects 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
235000013337 tricalcium citrate Nutrition 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
241000701366 unidentified nuclear polyhedrosis viruses Species 0.000 description 1
239000013598 vector Substances 0.000 description 1
235000013343 vitamin Nutrition 0.000 description 1
239000011782 vitamin Substances 0.000 description 1
229940088594 vitamin Drugs 0.000 description 1
229930003231 vitamin Natural products 0.000 description 1
239000001993 wax Substances 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
- C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Health & Medical Sciences (AREA)
Wood Science & Technology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Zoology (AREA)
Engineering & Computer Science (AREA)
Immunology (AREA)
Biochemistry (AREA)
Microbiology (AREA)
Molecular Biology (AREA)
Analytical Chemistry (AREA)
Biotechnology (AREA)
Physics & Mathematics (AREA)
Biophysics (AREA)
Bioinformatics & Cheminformatics (AREA)
General Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Enzymes And Modification Thereof (AREA)
Investigating Or Analysing Biological Materials (AREA)
Micro-Organisms Or Cultivation Processes Thereof (AREA)

JP2009541201A 2007-11-15 2008-11-17 γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法 Expired - Fee Related JP5580598B2 (ja)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US98820307P	2007-11-15	2007-11-15
US60/988,203		2007-11-15
PCT/JP2008/070864 WO2009064006A1 (fr)	2007-11-15	2008-11-17	PROCÉDÉ DE CRIBLAGE UTILISANT UN NOUVEAU SUBSTRAT EphA7 POUR LA γ-SECRÉTASE

Publications (2)

Publication Number	Publication Date
JPWO2009064006A1 JPWO2009064006A1 (ja)	2011-03-31
JP5580598B2 true JP5580598B2 (ja)	2014-08-27

Family

ID=40638851

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP2009541201A Expired - Fee Related JP5580598B2 (ja)	2007-11-15	2008-11-17	γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法

Country Status (4)

Country	Link
US (1)	US8530181B2 (fr)
EP (1)	EP2219028B1 (fr)
JP (1)	JP5580598B2 (fr)
WO (1)	WO2009064006A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP2177623A4 (fr) *	2007-07-19	2010-12-29	Eisai R&D Man Co Ltd	Procede de criblage utilisant c-met, un nouveau substrat pour la gamma-secretase
WO2009017234A1 (fr) *	2007-08-01	2009-02-05	Eisai R & D Management Co., Ltd.	Procédé de criblage utilisant le nouveau substrat c-ret pour la gamma-sécrétase
JP5580598B2 (ja)	2007-11-15	2014-08-27	エーザイ・アール・アンド・ディー・マネジメント株式会社	γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法
US7892769B2 (en) *	2007-11-30	2011-02-22	Eisai R&D Management Co., Ltd.	Processing of EphA4 polypeptide by γ-secretase activity
EP2653552B1 (fr)	2010-12-17	2016-10-19	Eisai R&D Management Co., Ltd.	PROCÉDÉ DE CRIBLAGE INDEXÉ SUR UNE RÉACTION DE CLIVAGE DE L'EphA4 PAR LA GÉLATINASE
EP2703814B1 (fr)	2011-04-25	2017-11-01	Eisai R&D Management Co., Ltd.	Méthode de détection d'une maladie neurologique associée à un dysfonctionnement cognitif impliquant la mesure du domaine extracellulaire epha4
NZ783106A (en)	2019-07-01	2025-08-29	Eisai R&D Man Co Ltd	Anti-epha4 antibody

Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2006056467A1 (fr) *	2004-11-25	2006-06-01	Cellzome Ag	Utilisation d'inhibiteurs du recepteur eph pour le traitement de maladies neurodegeneratives

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US255522A (en) *		1882-03-28		Valve for oil and water wells
CA1339413C (fr)	1988-06-24	1997-09-02	Junichi Miyazaki	Vecteur pour l'expression d'un gene exogene, renfermant un promoteur de gene .beta.-actine de poule
JP2824433B2 (ja)	1988-12-09	1998-11-11	財団法人化学及血清療法研究所	新規なハイブリッドプロモーターおよびこれを組み込んだ外来遺伝子発現用ベクター
JP3680114B2 (ja)	1993-09-17	2005-08-10	敏一中村	脳神経障害治療剤
US5902732A (en) *	1995-10-04	1999-05-11	Cytoscan Sciences Llc	Drug screening process measuring changes in cell volume
US20020068361A1 (en) *	1997-04-08	2002-06-06	Douglas Clary	Methods of evaluating specific cellular functions of receptor protein tyrosine kinases in a ligand independent manner
AU6887698A (en)	1997-04-08	1998-10-30	Sugen, Inc.	Study and treatment of diseases related to specific cellular functions of receptor protein tyrosine kinases
US5876946A (en) *	1997-06-03	1999-03-02	Pharmacopeia, Inc.	High-throughput assay
US20070026409A1 (en) *	2001-08-14	2007-02-01	The General Hospital Corporation	Nucleic acid and amino acid sequences involved in pain
US20060241074A1 (en) *	2001-08-14	2006-10-26	The General Hospital Corporation	Methods for treatment of pain
EP1478772A2 (fr)	2001-08-14	2004-11-24	The General Hospital Corporation	Sequences d'acides nucleiques et d'acides amines intervenant dans la douleur
JP2003169699A (ja)	2001-12-10	2003-06-17	Japan Science & Technology Corp	特異的γプロテアーゼ阻害剤のスクリーニング方法
JP2004000060A (ja)	2002-05-31	2004-01-08	Otsuka Pharmaceut Co Ltd	アミロイドβ産生に影響を与える化合物のスクリーニング方法
HRP20050461A2 (en)	2002-11-26	2005-08-31	Pharmacia & Upjohn Company Llc	Soluble notch-based substrates for gamma secretase and methods and compositions for using same
CN1878865A (zh)	2003-11-10	2006-12-13	财团法人大阪产业振兴机构	无细胞Notch切割分析方法以及药物筛选方法
US20070253954A1 (en)	2004-02-27	2007-11-01	Oncotherapy Science, Inc.	Epha4 As Therapeutic Target Of Prc And Pdaca
JP5094395B2 (ja)	2004-09-08	2012-12-12	ザユニバーシティーオブクイーンズランド	Ｅｐｈ受容体を調節することによる神経系内のグリオーシス、グリア瘢痕、炎症、または軸索成長阻害の処置
GB0427023D0 (en)	2004-12-09	2005-01-12	Merck Sharp & Dohme	Assay method
EP1947193A1 (fr) *	2007-01-17	2008-07-23	Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.	Procédé de criblage pour composés antidiabétiques
ATE546543T1 (de) *	2007-06-08	2012-03-15	Eisai R&D Man Co Ltd	Screening-verfahren mit verwendung des neuen substrats epha4 für gamma-sekretase
EP2183598A1 (fr) *	2007-07-13	2010-05-12	Elan Pharmaceuticals Inc.	Compositions et procédés permettant d'identifier la spécificité de substrat des inhibiteurs de la gamma secrétase
EP2177623A4 (fr) *	2007-07-19	2010-12-29	Eisai R&D Man Co Ltd	Procede de criblage utilisant c-met, un nouveau substrat pour la gamma-secretase
WO2009017234A1 (fr) *	2007-08-01	2009-02-05	Eisai R & D Management Co., Ltd.	Procédé de criblage utilisant le nouveau substrat c-ret pour la gamma-sécrétase
US20090163594A1 (en) *	2007-10-31	2009-06-25	Elan Pharmaceuticals, Inc.	Triple Assay System for Identifying Substrate Selectivity of Gamma Secretase Inhibitors
JP5580598B2 (ja)	2007-11-15	2014-08-27	エーザイ・アール・アンド・ディー・マネジメント株式会社	γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法
US7892769B2 (en) *	2007-11-30	2011-02-22	Eisai R&D Management Co., Ltd.	Processing of EphA4 polypeptide by γ-secretase activity
US20100113415A1 (en) *	2008-05-29	2010-05-06	Rajapakse Hemaka A	Epha4 rtk inhibitors for treatment of neurological and neurodegenerative disorders and cancer

2008
- 2008-11-17 JP JP2009541201A patent/JP5580598B2/ja not_active Expired - Fee Related
- 2008-11-17 US US12/742,312 patent/US8530181B2/en not_active Expired - Fee Related
- 2008-11-17 EP EP08849729A patent/EP2219028B1/fr not_active Not-in-force
- 2008-11-17 WO PCT/JP2008/070864 patent/WO2009064006A1/fr not_active Ceased

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2006056467A1 (fr) *	2004-11-25	2006-06-01	Cellzome Ag	Utilisation d'inhibiteurs du recepteur eph pour le traitement de maladies neurodegeneratives

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JPN6013046547; Ａｎａｓｔａｓｉｏｓ　Ｇｅｏｒｇａｋｏｐｏｕｌｏｓ，　Ｃｌａｕｄｉａ　Ｌｉｔｔｅｒｓｔ，　Ｅｎｒｉｃｏ　Ｇｈｅｒｓｉ，　ＬｉａＢａｋｉ，　ＣｈｉＪｉｅ　Ｘｕ，　Ｇｅｏ　Ｓｅｒｂａｎ　ａｎｄ　Ｎｉｋｏｌ *
JPN6013046549; ＨＯＬＭＢＥＲＧ　Ｊ，　ＣＬＡＲＫＥ　Ｄ　Ｌ，　ＦＲＩＳＥ　Ｎ　Ｊ，　Ｒｅｇｕｌａｔｉｏｎ　ｏｆ　ｒｅｐｕｌｓｉｏｎ　ｖｅｒｓｕｓａｄｈｅｓｉｏｎ　ｂｙ　ｄｉｆｆｅｒｅｎｔ　ｓｐｌｉｃｅ　ｆｏｒｍｓ *
JPN6013046552; Ｈｉｒｏｓｈｉ　Ｎａｋａｎｉｓｈｉ，　Ｔａｔｓｕｙａ　Ｎａｋａｍｕｒａ，　Ｅｌｉ　Ｃａｎａａｎｉ，　ａｎｄ　Ｃａｒｌｏ　Ｍ．Ｃｒｏｃｅ，　ＡＬＬ１　ｆｕｓｉｏｎ　ｐｒｏｔｅｉｎｓ　ｉｎｄｕｃｅ　ｄｅｒ *
JPN6013046553; Ｊ　Ｂｉｏｌ　Ｃｈｅｍ　Ｖｏｌ．２８２　Ｎｏ．２２　Ｐａｇｅ．１６１５５-１６１６３　（２００７．０６．０１） *
JPN6013046555; Ｍｉｃｈａｅｌ　Ｐａｕｌ　Ｍｕｒｐｈｙ，　Ｌｅｓｌｅｙ　Ｊｉｌｌ　Ｈｉｃｋｍａｎ，　Ｃｈｒｉｓｔｏｐｈｅｒ　ＢｅｎｊａｍｉｎＥｃｋｍａｎ，Ｓａｃｈａ　Ｎｏｅｌｌｅ　Ｕｌｊｏｎ，　Ｒｏｎｇ　Ｗａｎｇ， *

Also Published As

Publication number	Publication date
JPWO2009064006A1 (ja)	2011-03-31
EP2219028B1 (fr)	2012-09-12
US20100255522A1 (en)	2010-10-07
WO2009064006A1 (fr)	2009-05-22
EP2219028A1 (fr)	2010-08-18
US8530181B2 (en)	2013-09-10
EP2219028A4 (fr)	2010-12-29

Publication	Publication Date	Title
JP5511377B2 (ja)	2014-06-04	γ−セクレターゼの新規基質ＥｐｈＡ４を利用したスクリーニング方法
JP5508857B2 (ja)	2014-06-04	新規活性を有するＥｐｈＡ４ポリペプチドおよびその用途
JP5580598B2 (ja)	2014-08-27	γ−セクレターゼの新規基質ＥｐｈＡ７を利用したスクリーニング方法
Kim et al.	2002	Nectin-1α, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/γ-secretase-like cleavage
US6713276B2 (en)	2004-03-30	Modulation of Aβ levels by β-secretase BACE2
JPWO2009011426A1 (ja)	2010-09-24	γ−セクレターゼの新規基質ｃ−Ｍｅｔを利用したスクリーニング方法
JP6059017B2 (ja)	2017-01-11	ゼラチナーゼによるＥｐｈＡ４の切断反応を指標としたスクリーニング方法
CA2605410A1 (fr)	2006-10-26	Agent therapeutique destine a des troubles associes a la proteine .beta. amyloide
JP2003512043A (ja)	2003-04-02	Ａｓｐ２の阻害剤のスクリーニング方法
JPWO2009017234A1 (ja)	2010-10-28	γ−セクレターゼの新規基質ｃ−Ｒｅｔを利用したスクリーニング方法
JP2003512080A (ja)	2003-04-02	Ａｓｐ１の阻害剤のスクリーニング方法
Ritz et al.	2009	Cortical and putamen age-related changes in the microvessel density and astrocyte deficiency in spontaneously hypertensive and stroke-prone spontaneously hypertensive rats
JP2012039881A (ja)	2012-03-01	γ−セクレターゼの新規基質ＰｌｅｘｉｎＡ２を利用したスクリーニング方法
JP2012039882A (ja)	2012-03-01	γ−セクレターゼの新規基質ＰｌｅｘｉｎＡ４を利用したスクリーニング方法
CA2613082A1 (fr)	2007-01-04	Methode d'identification de modulateurs de rufy2 utiles pour traiter la maladie d'alzheimer

Legal Events

Date	Code	Title	Description
2011-11-11	A621	Written request for application examination	Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20111110
2013-09-25	A131	Notification of reasons for refusal	Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130924
2014-06-24	TRDD	Decision of grant or rejection written
2014-07-02	A01	Written decision to grant a patent or to grant a registration (utility model)	Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140701
2014-07-17	A61	First payment of annual fees (during grant procedure)	Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140711
2014-07-18	R150	Certificate of patent or registration of utility model	Ref document number: 5580598 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150
2021-07-18	LAPS	Cancellation because of no payment of annual fees